2-Naphthalenecarboxaldehyde → HCID 66748221, compound

Temperature

-25 °C

A dry, nitrogen flushed flask, equipped with a stirbar and septum, was charged with 2,2,6,6-tetramethylpiperidinylmagnesium chloride.lithium chloride in tetrahydrofuran (1.0M, 1.21 mL, 1.21 mmol). The flask was cooled to −25° C. and a solution of ethyl 5-pyridin-4-ylthiophene-2-carboxylate (0.257 g, 1.10 mmol) in tetrahydrofuran (1.0 mL, 12 mmol) was added dropwise with stirring. The resulting dark reddish orange solution was stirred at −25° C. for 30 minutes. 2-Naphthalenecarboxaldehyde (0.172 g, 1.10 mmol) was then added dropwise (as a solution in 1.5 ml THF)— the reaction mixture became purple. The reaction was stirred at −25° for 5 minutes, then the cooling bath was removed and the reaction was allowed to warm to room temperature with stirring. An aliquot was removed from the reaction and quenched into sat. NH4Cl solution, then extracted with ethyl acetate. A LCMS of this extract indicated that all starting material had been consumed and that the major peak had correct mass for the desired product. The reaction was quenched by the slow dropwise addition of a saturated ammonium chloride solution (5 ml). The resulting yellow-orange mixture was transferred to a reparatory funnel and diluted further with water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The extracts were combined, washed with saline, dried, and evaporated to leave crude product as an orange oil which was dissolved in minimal dichloromethane then was purified by column chromatography on silica gel (gradient 100% DCM to 5% MeOH in ethyl acetate) to afford product 210 mg (49% yield) as a white foam. LC/MS (FA) ES+ 390. 1H NMR (400 MHz, DMSO) δ 8.63-8.58 (dd, J=4.6, 1.6 Hz, 2H), 8.04-8.00 (s, 1H), 8.00-7.96 (s, 1H), 7.87-7.81 (d, J=8.7 Hz, 3H), 7.76-7.71 (dd, J=4.6, 1.7 Hz, 2H), 7.62-7.58 (d, J=1.6 Hz, 1H), 7.50-7.45 (t, J=3.0 Hz, 2H), 6.74-6.69 (d, J=4.2 Hz, 1H), 6.33-6.28 (d, J=4.2 Hz, 1H), 4.37-4.31 (dd, J=7.1, 4.3 Hz, 2H), 1.35-1.27 (t, J=7.1 Hz, 3H).

1. customA dry, nitrogen flushed flask, equipped with a stirbar and septum
2. stirringThe resulting dark reddish orange solution was stirred at −25° C. for 30 minutes
3. stirringThe reaction was stirred at −25° for 5 minutes
4. customthe cooling bath was removed
5. temperatureto warm to room temperature
6. stirringwith stirring
7. customAn aliquot was removed from the reaction
8. customquenched into sat. NH4Cl solution
9. extractionextracted with ethyl acetate
10. customhad been consumed and that the major peak
11. customThe reaction was quenched by the slow dropwise addition of a saturated ammonium chloride solution (5 ml)
12. customThe resulting yellow-orange mixture was transferred to a reparatory funnel
13. additiondiluted further with water and ethyl acetate
14. customThe organic layer was separated
15. extractionthe aqueous layer was further extracted with ethyl acetate
16. washwashed with saline
17. customdried
18. customevaporated
19. customto leave crude product as an orange oil which
20. customthen was purified by column chromatography on silica gel (gradient 100% DCM to 5% MeOH in ethyl acetate)

ORD record

ord-dd01b5b723814020ba9413cb7e716fa6

Source dataset

uspto-grants-2014_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08796271B2